Drugs for the treatment of cancer and other diseases have a so-called “therapeutic window”. In the case of cancer, the therapeutic window defines the drug dosage that can kill cancer cells preferentially to normal cells, thereby establishing a safety range for the use of the drug. The therapeutic window for conventional chemotherapeutics is narrow with, in many cases, significant adverse effects coinciding with marginal slowing of tumour growth. Targeted treatments that spare normal cells are urgently needed.
Therapeutic antibodies form a newer class of cancer therapies that specifically target an antigen presented on the surface of cancer cells. When the target surface protein is unique to the cancer cell, adverse antibody effects on normal cells can be avoided. However, for the majority of antigens, target expression is not restricted completely to tumour cells, with some normal cells also expressing the antigen. In these cases, the antibody may have an effect on normal cells as well as tumor cells, leading to “on-target, off-tissue” adverse events. In the case of the EGFR antigen, because of its ubiquitous presence on the surface of normal cells such as keratinocytes as well as on cancer cells, the clinical use of EGFR-targeting therapeutics is associated with adverse events that include severe rash.
Considering the efficacy of anti-EGFR therapies in treating patients that overexpress EGFR, the risk associated with severe skin reaction is currently considered acceptable when managed properly. The risk of anti-EGFR therapy-associated toxicity can be reduced by prior administration of anti-histamine, or by administering anti-EGFR antibody at a reduced and less effective dose.
Efforts to improve upon EGFR antibodies are aimed at generating antibodies having even greater affinity for the target antigen. In WO 2006/009694 published 26 Jan. 2006, Kussie et al describe the crystal structure of the interaction between EGFR and cetuximab Fab fragment, and identify residues that may be modified to improve the effectiveness of cetuximab as an EGFR antagonist.
It would be desirable to provide an EGFR antibody that is useful to treat subjects presenting with EGFR over-expressing disease cells, while avoiding significant interaction with tissues including skin and particularly keratinocytes and other cells that also present the EGFR antigen at normal levels.
It is an object of the present invention to provide therapeutic antibodies, and fragments and conjugates thereof that bind effectively to a given target only when that target is presented at a relatively higher density characteristic of a disease state.
It is a further object of the present invention to provide such antibodies, fragments and conjugates in pharmaceutical compositions, particularly for therapeutic and diagnostic use.
It is a further object of the present invention to provide a method useful, in a subject in need thereof, to control the growth of disease cells that present EGFR at a density greater than normal EGFR density, while avoiding or minimizing adverse effects on normal cells.